Small molecule drugs continue to be an important part of medical therapy. However, their use is plagued by the onset of unexpected side effects, often seen only in late-stage clinical trials or after release to the market. As a result, there have been a number of high profile drug withdrawals because of side effects. More worrisome, however, are side effects that result from drug-drug interactions (DDIs). It is very difficult to empirically study DDIs before drugs enter the market because of the small samples of co-prescribed drugs in most late stage clinical drug (Phase III) studies. Some DDIs can be predicted based on knowledge of shared pathways of metabolism--such as when two drugs share a metabolizing enzyme and so the effective levels of one or both drugs are affected by saturation of the enzyme. But many DDIs are more idiosyncratic and difficult to predict. The most difficult cases are those in which two drugs produce a synergistic effect not seen with either drug alone. Thus, I created surveillance methods to detect unexpected DDIs, relying on clinical databases--both electronic medical records and spontaneous adverse event reporting systems. Understanding DDIs has an additional benefit for drug discovery. If two drugs have a synergistic effect, they may shed new light on the molecular mechanisms of their action or of the diseases they treat. If we use a model not of "one drug-one target" but of multiple interacting cellular pathways that respond to drugs ("the network is the target"), then we can leverage DDIs for the study of disease. However, to do this we need new ways to probe and understand these pathways, such as studying the unexpected synergies between drugs in observational reporting systems. Thus it would be extremely valuable to have computational methods that link adverse events to molecular events. The emergence of large databases linking drugs, diseases, drug effects, demographics and genes offers a new opportunity to create informatics methods for greater understanding small molecule effects at the clinical and biological level. I describe studies in which I have shown the great power of integrating these databases. In particular, I used the FDA Adverse Events Reporting System (FDA-AERS) to discover a signal for abnormal glucose in patients taking both paroxetine and pravastatin. Paroxetine is a selective serotonin reuptake inhibitor antidepressant. Pravastatin is an HMG CoA reductase inhibitor cholesterol-lowering drug. Neither is typically associated with hyperglycemia. Based on my analysis of the FDA-AERS, I examined patient electronic medical records in three separate hospitals (Stanford, Harvard, Vanderbilt), and demonstrated a striking increase in glucose levels on patients on both drugs, compared to their glucose levels on only one of the drugs. I also showed that mice on these two drugs have increased glucose. I am working with FDA to consider a potential update to the drug labels. Although this discovery illustrates the power of clinical data mining, the databases I used are filled with biases that make their use treacherous. I believe there are many similarly valuable discoveries to be made in these databases. However, only with careful attention to systematic biases can I ensure that the predictions I make are valid. In this thesis I describe methods to address the major informatics challenges to detecting and understanding the effects of taking multiple drugs at once. In particular, I have shown that I can (1) remove the bias introduced by unmeasured confounding variables, (2) improve the detection of drug interactions in cases of low or even non-reporting, (3) link drug effects to genes through chemical informatics methods, and (4) validate new drug effects using novel retrospective and prospective studies. The work forms an infrastructure that is useful to (1) pharmacogenomics scientists wishing to understand drug action at the molecular level, (2) pharmacologists wishing to better understand the effects of drugs singly and in combination, and (3) regulatory agencies wishing to understand the efficacy and safety of drugs and drug-interactions at a population level.

Data is revolutionizing the healthcare industry. With more data available than ever before, and applying the right analytics you can spur growth. Benefits extend to patients, providers, and board members, and the technology can make centralized patient management a reality. Despite the potential for growth, many in the industry and government are questioning the value of data in health care, wondering if it's worth the investment. This book tackles the issue and proves why BI is not only worth it, but necessary for industry advancement. Madsen challenges the notion that data has little value in healthcare, and shows how BI can ease regulatory reporting pressures and streamline the entire system as it evolves. She illustrates how a data-driven organization is created, and how it can transform the industry. -- Edited summary from book.

Recent work in the fields of cancer research, stem cell biology, and immunology have highlighted the role of specific cellular subsets in disease development and progression. However, many high-throughput assays (i.e. microarrays) used to study diseases of the cell quantify molecular targets in bulk tissue samples, thereby obfuscating signal from functionally distinct cellular subsets. Single-cell measurement technologies such as flow cytometry quantify levels of molecular targets and other cellular properties in single cells, thereby enabling the identification, isolation, and investigation of specific cellular subpopulations. Currently, fluorescence-based flow cytometers permit the concurrent measurement of 12 to 17 molecular targets per cell, thus greatly restricting flow cytometry's utility in screening and target discovery studies. Recent instrumentation advancements, specifically mass cytometry, have increased the number of parameters that are simultaneously measurable using flow cytometry to over 40. Additionally, multiplexing techniques such as mass tag cell barcoding have enabled the concurrent measurement of samples subjected to dozens of experimental conditions. While technological and protocol advancements have now made flow cytometry an attractive assay for screening and discovery, methods for analyzing resulting data have not made equivalent progress. Specifically, hypothesis-driven manual analyses remain standard practice for analyzing flow cytometry data, yet these techniques are biased and do not scale to higher-dimensional data or experiments with many samples. There is a clear need for methods that facilitate scalable and thorough investigation of high-dimensional single cell datasets. The central theme of this dissertation is the development, evaluation, and application of data-driven methods for analyzing high-dimensional, single cell measurements. Among other contributions, we presents a novel method, termed Citrus, that identifies relevant cell subsets in multidimensional flow cytometry data. Cell subsets are identified by Citrus using a novel objective, experimental-relevance, as opposed to many existing automated methods that are optimized for reproducing the results of manual population identification efforts. We start by showing Citrus to be sensitive identifier of manually identified populations in five publicly available datasets. Next, Citrus' capacity to identify experimentally-informative cellular subsets is confirmed by identifying and validating blood cells that respond to B cell receptor cross-linking. Citrus' performance is compared to an existing data-driven method wherein we find our methods are better able to identify rare prognostic cell subsets in HIV-infected patients. Finally, we close with a proposed application of Citrus to a novel dataset in which we aim to evaluate the immune system's role and response to surgically induced tissue trauma. Importantly, our methods scale well to higher dimensional datasets with many patients and require no knowledge of existing cellular subsets. Furthermore, these methods are easily applied in diverse experimental settings, and provide interpretable results that facilitate hypothesis generation. Thus we anticipate that the methods presented here will aid investigators in the performance of unbiased, and potentially more thorough investigation of complex, high-dimensional single-cell datasets.

This dissertation develops data-driven methods for healthcare risk modeling to facilitate risk identification and evaluation, focusing on post-marketing drug safety surveillance and breast cancer incidence prediction. For risk identification, we first propose a novel methodology for post-marketing drug safety surveillance: "Follow the money'', which monitors cost in health insurance claims data to detect increased spending related to adverse drug events (ADE). By using real claims data from 2.4 million insured individuals, we demonstrate that this method enables early detection of signals of ADE. Second, we recommend statistical study designs to detect rare and time-dependent ADE resulting from long-term drug use and highlight statistical considerations that drug surveillance designers should focus on when implementing a long-term surveillance. We characterize statistical properties and compare performances of a variety of surveillance designs by applying them to simulated event data as well as real health insurance claims data. For risk evaluation, we develop a stochastic simulation model of the Surveillance, Epidemiology and End Results database to quantify the impact of menopausal hormone therapy (MHT) on U.S. breast cancer incidence. Our model quantifies the promoting effect of MHT on breast tumor growth and the reduced mammographic detectability. By modeling unobservable tumor natural history dynamics and simulating individual life history at a population level, we evaluate the contribution of MHT use cessation to the observed decline in breast cancer incidence between 2002 and 2003. We also predict U.S. breast cancer incidence in the absence of MHT.

RWJF and the Advisory Committee hosted a listening tour of five "Learning What Works" events in diverse cities across the country: Philadelphia; Phoenix; Des Moines, Iowa; San Francisco; and Charleston, South Carolina. A broad spectrum of individuals--from health care providers to researchers to community service providers to business leaders interested in using data to improve their health and the health of their communities--attended these five events. The forums generated key observations and examples, as well as many questions around using, exchanging, and protecting data and what individuals and communities want and need in order to improve health or foster connections between different sectors. These observations provided the basis for the Advisory Committee's findings and recommendations, which are detailed in this report.

The human gut microbiome teems with a dizzying array of microbial flora. Recent studies have demonstrated a causal relationship between microbial diversity and clinical phenotypes such as obesity and cardiovascular disease. Current analytical methods in the field excel at answering "who is there" in terms of the microbial population, yet are limited in answering "what are they doing". In particular, for dysbiosis of the human distal gut, we desire an understanding of microbial community structure at the biochemical level. My approach to revealing the biochemistry of the human microbiome consists of: 1) enhancing single-cell isolate genomes with metagenomic reads, 2) generating hundreds of microbiome-wide metabolic reconstructions spanning thousands of enzymatic reactions, and 3) creating a new modeling framework for complex microbial communities. I will first discuss a new method for recovering a complete genome from a single-cell experiment when there is insufficient coverage from the single-cell reads alone. This new method, called "Barrel of Monkeys", enables the efficient combination of both single-cell and metagenomic reads, with an accuracy of 99%. I demonstrate this method on four isolates of the enigmatic phylum TM7. I then annotate and perform metabolic reconstruction on novel genomes, to shed light on the biology of these organisms. Next, I will review a pipeline for comparative analysis of microbiome metabolic reconstructions, termed the GutCyc Collection. The utility of GutCyc will be motivated in a few vignettes, ranging from applications in metabolic route discovery in cardiovascular disease to pharmaco-microbiomics. Finally, I have modeled the human gut as a set of distinct microbial guilds in order to understand their biochemical thermodynamics. Guilds, or trophic species, are microbial equivalence classes where guild members share the same carbon source, nitrogen source, electron donor, and electron acceptor. I will review the details of a novel methodology for guild identification from reference microbial genomes, a pipeline for normalized abundance computation, and formulation of multi-guild biochemical mass balance equations. I will demonstrate the utility of this approach with applications in data mining and in thermodynamic modeling of an obesity microbiome dataset.

"Data mining has rapidly emerged as an enabling, robust, and scalable technique to analyze data for novel patterns, trends, anomalies, structures, and features that can be employed for a variety of biomedical and clinical domains. Approaching the techniques and challenges of image mining from a multidisciplinary perspective, this book presents data mining techniques, methodologies, algorithms, and strategies to analyze biomedical signals and images. Written by experts, the text addresses data mining paradigms for the development of biomedical systems. It also includes special coverage of knowledge discovery in mammograms and emphasizes both the diagnostic and therapeutic fields of eye imaging"--Provided by publisher.

"This hands-on book uses practical examples to illustrate the power of R and data mining. Assuming no prior knowledge of R or data mining/statistical techniques, it covers a diverse set of problems that pose different challenges in terms of size, type of data, goals of analysis, and analytical tools. The main data mining processes and techniques are presented through detailed, real-world case studies. With these case studies, the author supplies all necessary steps, code, and data. Mirroring the do-it-yourself approach of the text, the supporting website provides data sets and R code" -- Provided by publisher.

The structure of the normal brain and its imaging appearance -- The general appearance of edema and hemorrhage on CT, MR and US (including a general introduction to CT, MR and US scanning) -- The basics of contrast and its role in dating -- How the imaging appearance of edema and hemorrhage change over time on CT, MR, and US: dynamic (acute) dating -- Patterns of parenchymal injury: pattern (chronic) dating -- Principles of dynamic dating in the medical legal setting -- Principles of pattern dating in the medical legal setting -- Therefore, what can be said based on the images, and what can't be said based on the images -- The root causes of uncertainty in dating neurologic events based on imaging findings.

More than two million medical students, doctors and other health professionals from around the globe have owned a copy of Davidson's Principles and Practice of Medicine since it was first published. Today's readers rely on this beautifully illustrated text to provide up-to-date detail of contemporary medical practice, presented in a style that is concise and yet easy to read. Davidson's provides the factual knowledge required to practise medicine, explaining it in the context of underlying principles, basic science and research evidence, and shows how to apply this knowledge to the management of patients who present with problems rather than specific diseases. The book has won numerous prizes including being highly commended in the British Medical Association book awards. Davidson's global perspective is enhanced by the input of an international team of authors and a distinguished International Advisory Board from 17 countries. Building on the foundations laid down by its original editor, Davidson's remains one of the world's leading and most respected textbooks of medicine. The underlying principles of medicine are described concisely in the first part of the book, and the detailed practice of medicine within each sub-specialty is described in later system-based chapters. Most chapters begin with a two-page overview of the important elements of the clinical examination, including a manikin to illustrate the key steps in the examination of the relevant system. A practical, problem-based clinical approach is described in the 'Presenting Problems' sections, to complement the detailed descriptions of each disease. The text is extensively illustrated, with over 1000 diagrams, clinical photographs, and radiology and pathology images. 1350 text boxes present information in a way suitable for revision, including 150 clinical evidence boxes summarising the results of systematic reviews and randomised controlled trials and 65 'In Old Age' boxes highlighting important aspects of medical practice in the older population. A combined index and glossary of medical acronyms contains over 10 000 subject entries. The contents can also be searched comprehensively as part of the online access to the whole book on the StudentConsult platform. Access over 500 self-testing questions with answers linked to the book's content for further reading. The text uses both SI and non-SI units to make it suitable for readers throughout the globe.

This website presents Andreas Vesalius' Renaissance anatomical atlas On the Fabric of the Human Body (1543, 1555) in an exciting new way and explains the work in progress at Northwestern University to translate and annotate this historic work.

Although cancer types vary widely, the number of new cancer drugs each year is severely limited. Even for those cancer therapies which are currently in use, prognostic outcomes vary significantly across cancer types. Drug discovery relies primarily on our knowledge of direct drug targets, but not the systematic off-target effects that these therapies may have. As a result, our knowledge of these drugs is somewhat limited to general mechanistic classes. Within these classes it is hard to find potential patient differences without time-intensive studies and trials. While drug classification relies on our knowledge of direct targets, it does not typically consider how a number of global cellular processes are ultimately affected. Quantifying the mechanistic differences between drugs is a difficult process. Current standards to quantify individual drug efficacy are large-scale measurements are taken at a heterogeneous population level, ignoring the effects of drug action or mechanism in single cells or cell populations. Because our knowledge is limited in this way, we are often surprised to find that similarly classified cancer drugs can have disparate effects in patients. Single-cell technologies including flow cytometry allow us to uncover relationships between drugs through simultaneous measurement of cell signal, cell cycle and cell type for each cell. Recent technological advances in flow cytometry have facilitated new clinical tests to determine cancer subtypes. In addition, these methodological advances have created potential for providing novel insights into drug mechanism and patient response. In this dissertation, I describe a new framework for performing mechanistic profiling of cancer cells. There are two facets of this problem. The first is an understanding of cancer cell cycle. Prior to treating with a drug, it is important to form a general model of how a cancer cell replicates. In a screening methodology, however, this is a difficult problem. I address this problem by building an automated, de novo model of cell cycle. Second, I perform cancer therapeutic profiling by measuring DNA damage, apoptosis, cell cycle, and cell signaling markers across multiple cancer cell types. In this thesis, I combine both cell cycle and drug profiling methods into a new drug profiling framework that can be used to find existing and novel cell cycle and drug-based biology. The results of our current work have major implications for use in profiling aberrant cell types in primary cancer samples, as well as mechanistic drug screening.

Despite advances in health care, infectious microbes continue to be a formidable adversary to scientists and doctors. Vaccines and antibiotics, the mainstays of modern medicine, have not been able to conquer infectious microbes because of their amazing ability to adapt, evolve, and spread to new places. Terrorism aside, one of the greatest dangers from infectious disease we face today is from a massive outbreak of drug-resistant microbes. Deadly Outbreaks recounts the scientific adventures of a special group of intrepid individuals who investigate these outbreaks around the world and figure out how to stop them. Part homicide detective, part physician, these medical investigators must view the problem from every angle, exhausting every possible source of contamination. Any data gathered in the field must be stripped of human sorrows and carefully analyzed into hard statistics. -- Jacket.

Deafness explores the neuronal consequences of being deaf on the peripheral and the central nervous system as well as on cognition and learning, viewed from the standpoint of genetics, neuroanatomy and neurophysiology, molecular biology, systems neuroscience, and cognitive neuroscience.

Miller and Truog challenge fundamental doctrines of established medical ethics. They argue systematically that physicians legitimately cause the death of patients in the routine practices of withdrawing life support and vital organ donation.

Death and Dying in Modern Britain -- Palliative Care Philosophy and Practice -- Hospice Development in the UK -- Spirituality -- Understanding Grief -- Supporting Bereaved People -- Issues for Policy and Practice.

As we think about death -- What is death? -- The death system -- Dying -- Hospice and palliative care -- End-of-life issues and decisions -- Suicide -- Violent death : murder, terrorism, genocide, disaster, and accident -- Euthanasia, assisted death, abortion, and the right to die -- Death in the world of childhood -- Bereavement, grief, and mourning -- The funeral process -- Do we survive death? -- How can we help? -- Good life, good death?

"The true story of the war on cancer from one of its generals In The Death of Cancer, Dr. Vincent T. DeVita Jr.--former director of the National Cancer Institute, former physician-in-chief at Memorial Sloan Kettering, director of the Yale Cancer Center, former president of the American Cancer Society, and developer of the first successful chemotherapy treatment for Hodgkin's lymphoma, which first demonstrated that advanced cancers of a major organ system in adults could be cured by chemotherapy--provides a personal history of one of the greatest science stories of our time, covering our fight against cancer from a man who's seen it all. But this is more than a history; it's also a work of advocacy. Despite declining mortality rates, DeVita argues, America's cancer patients are being shortchanged by timid doctors, misguided national agendas, and compromised bureaucracies. He gives readers an eye-opening look at the strengths and weaknesses of America's most prestigious cancer centers, showing how patients can use this information to their advantage. Though we're rapidly approaching total victory over cancer, he contends, we need to do more to synthesize our progress and help doctors put it into practice. This is an ambitious book about a life-or-death subject, a vital entry into the cancer literature genre. With historical depth and authenticity, DeVita brings important information to readers about what cancer is, how best to fight it, and what we still have to learn"-- Provided by publisher.

1. A pragmatic method -- 2. A pragmatic framework of values and principles: the beginning -- 3. Defining and valuing properties and individuals -- 4. What harm does death do to the decedent? -- 5. How should we feel about our own death? -- 6. How should we feel about another's death? -- 7. Is there a duty to die? -- 8. A duty to suicide -- Index.

Current economic, demographic, and environmental shifts are presenting major challenges to health care systems around the world. In response, decentralization--the transfer of control from central to local authorities--is emerging as a successful means of meeting these challenges and reducing inequities of care. But as with health care itself, one size does not fit all, and care systems must be responsive to global reality as well as local demand. Decentralizing Health Services explores a variety of applications of decentralization to health care delivery in both the developing and developed worlds. Outfitted with principles, blueprints, and examples, this ambitious text clearly sets out the potential role of decentralized care as a major player in public health. Its models of service delivery illustrate care that is effective, inclusive, flexible, and in tune with the current era of preventive and evidence-based healthcare. Contributors point out opportunities, caveats, and controversies as they: Clarify the relationships among decentralization, politics, and policy Differentiate between political, fiscal, and administrative decentralization in health care systems. Consider public/private partnerships in health systems. Explain how the effects of decentralization can be evaluated. Present the newest data on the health outcomes of decentralization. Explore some challenges and global issues of health systems in the 21st century. And each chapter features learning goals, discussion questions, activities, and recommendations for further reading. Heralding changes poised to revolutionize care, Decentralizing Health Services will broaden the horizons of researchers and administrators in health services, health economics, and health policy.

Limb threatening trauma to the leg may be treated with either limb salvage (retention process) or amputation (prosthetic process). Limb salvage allows the patient to keep his leg and avoid using a prosthetic; however, it typically has higher probabilities than amputation of complications, additional time in the hospital, and chronic pain. The optimal treatment is still under debate and the current methods to make the decision do not explicitly incorporate the patient's preferences or the patient's medical insurance. This dissertation develops a decision analysis model to help a patient think clearly about the retention process vs. the prosthetic process. The model updates conditional probabilities of various outcomes based on the patient's demographics and develops a method to explicitly incorporate the patient's preferences for keeping the leg, avoiding chronic pain, and avoiding time in the hospital. The model also calculates the probabilities of hospital and prosthetic costs for the patient's health insurance and risk attitude. The decision analysis model in this dissertation utilizes preferences from the patient to inform the decision, facilitates effective discussions between the doctor and the patient, and provides a comprehensive recommendation to the patient.

This well-established international series examines major areas of basic and clinical research within neuroscience, as well as emerging and promising subfields.This volume explores interdisciplinary research on decision making taking a neural and behavioural approach *Leading authors review the state-of-the-art in their field of investigation, and provide their views and perspectives for future research *Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered *All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist.

"The art and science of spinal surgery has been in constant evolution since the early middle ages. The majority of advances, however, have occurred after World War II with the advent of antibiotics, better imaging, improved diagnostic methods, and surgical care. In the past five to ten years, a greater understanding of spinal anatomy and the development of more sophisticated radiological imaging and instrumentation have further illuminated what is possible in spinal care. Decision Making in Minimally Invasive Spine Surgery adds to the historical continuum by compiling a collection of chapters that define why a minimally invasive approach should be chosen and how to perform such a procedure, written by authors who have established themselves as experts in the field"--Provided by publisher.

From important aspects of the physical examination to imaging studies to treatment options and dosage guidelines, this book provides a solid introduction to the evidence-based management of patients in the neurological intensive care unit. Succinct text in a highly accessible bullet-point format details the essentials of history-taking, physical examination, differential diagnosis, diagnostic evaluation, and treatments for a range of neurological problems in the critical care setting.

"Decision Making in Spinal Care, 2nd Edition presents current management strategies for the most common spine problems, including trauma injuries, metabolic and degenerative diseases, and spinal deformities. Each chapter opens with a concise introduction to the topic and discussion of the classification of the injury, condition, or management approach. The authors then describe the diagnostic workup of the patient, the treatment options available, the likely outcome, and possible complications. Chapters also include useful decision making algorithms"--Provided by publisher.

A look at the recent oncology literature or a search of one of the common databases reveals a steadily increasing number of nomograms and other prognostic models, some of which are also available in the form of web-based tools. These models may predict the risk of relapse, lymphatic spread of a given malignancy, toxicity, survival, et cetera Pathology information, gene signatures, and clinical data may all be used to compute the models. This trend reflects increasingly individualized treatment concepts and also the need for approaches that achieve a favorable balance between effectiveness and side-effects. Moreover, optimal resource utilization requires prognostic knowledge, for example to avoid lengthy and aggressive treatment courses in patients with a short survival expectation. In order to avoid misuse, it is important to understand the limits and caveats of prognostic and predictive models. This book provides a comprehensive overview of such decision tools for radiation oncology, stratified by disease site, which will enable readers to make informed choices in daily clinical practice and to critically follow the future development of new tools in the field.

Bloodletting and inflammation -- Bloodletting and social norms -- Disease and causes of disease in early nineteenth century medical thought -- The Early nineteenth century conception of quackery -- The Edinburgh bloodletting controversy -- Ignaz Semmelweis and the adoption of etiological concepts of disease -- The Collapse of traditional medicine and the rise of medical science -- The Current crisis in epidemiology.

Preface: the sacred part -- Methodological introduction: a strategy and protocol of deconstruction -- Dignity and sanctity -- Dignity and sovereignty -- Human dignity from Cicero to Kant -- The right to die: mapping a contemporary debate -- Suicide and sacrifice from Plato to Kant -- Sacrifice and the right to die -- A debate deconstructed.

The pancreas consists of hormone-secreting endocrine cells, zymogen-producing acinar cells, and bicarbonate-secreting duct cells. Understanding their respective development is essential for developing strategies to derive precious cell types such as insulin-producing [beta] cells for treatment of diabetes mellitus. This thesis explores pancreas development using a systems-based approach to discover regulators and biological gene sets that contribute to cell differentiation, lineage specification, and endocrine-cell maturation. In Chapter 2, we describe the use of cell purification to obtain rare cell populations such as pancreatic progenitors from the native mouse pancreas. We query the transcriptome of 12 cell populations and discover previously unrecognized gene sets or modules that influence duct-cell biology and endocrine maturation. Using a reiterative approach, we identify and prioritize transcription factor regulators and their co-regulated modules. Using appropriate mutant mice, we validate the role of four novel regulators (Prdm16, Runx1t1, Etv1, and Bcl11a) and their effect on endocrine development. In Chapter 3, we describe the use of a pancreatic sphere culture system that can be scaled to phenotypically assess the effect of novel regulators on endocrine development. Lastly, we conclude with a framework for building gene regulatory networks (GRNs) from expression-based data and literature mining. Our goal is that a more global view of pancreas development will provide a framework for understanding the diversity and dynamics of pancreas formation.

This thesis is composed of experimental and analytic work deconstructing the cerebellar learning algorithm. The central finding is that two parallel neural circuits, with independent instructive signals, support cerebellum-dependent learning. An analytic framework for this result, based on overcoming signal-dependent noise, is proposed.

The ultimate goal of regenerative medicine is to repair tissues damaged by aging, injury or disease. Tissue-specific adult stem cells constitute a reservoir of cells in postnatal tissue that have the remarkable capacity to proliferate and repair tissue damage because they can both self-renew, or produce more stem cells, and differentiate into mature cells. Adult stem cells have been identified in a variety of tissues, including blood, brain, skin, intestine, and muscle and methods exist to prospectively isolate these populations by flow cytometry. Upon transplantation, they possess an extraordinary ability to contribute extensively to tissue regeneration. Notably, adult stem cells are a relatively rare cell population and methods to propagate and expand these cell types in culture without loss of regenerative capacity are lacking, a hurdle to their clinical use. In vivo, stem cells reside in an instructive microenvironment, or niche, which serves to regulate fate decisions, including quiescence, self-renewal, and differentiation. Given the complexity of their native environment, it is not surprising that upon removal from their niche they rapidly lose regenerative capacity. While the role of biochemical signals in regulating stem cell fate and function has been widely explored, the effects of biophysical signals have not been discerned. To elucidate the role of matrix elasticity in regulating adult stem cell fate, we first design a biomimetic hydrogel culture platform to mimic tissue elasticity and physiologic presentation of biochemical cues. Adapting a previously described conjugate addition reaction, poly(ethylene glycol) hydrogel substrates are fabricated which have a Young's modulus that is tunable in the physiologic range (1-50kPa). Gels are designed to have limited post-polymerization swelling to enable constant density of tethered biological ligands. Utilizing this tunable hydrogel culture platform, we provide the first definitive evidence that matrix elasticity regulates adult stem cell self-renewal in culture. Using a combination of culture studies and in vivo functional assays in mice, we demonstrate that substrate rigidity profoundly impacts the self-renewal potential of tissue-specific adult stem cells isolated from skeletal muscle and bone marrow. In contrast with rigid tissue culture plastic in which regenerative potential is lost, we demonstrate that culture on a pliant hydrogel substrate maintains the 'stemness' of muscle stem cells (MuSCs) and hematopoetic stem cells (HSCs). Further, we describe a novel in vivo screen and identify an extracellular matrix molecule which, in conjunction with soft hydrogel, has a previously unrecognized role in regulating HSC fate. These studies demonstrate that recapitulating tissue rigidity, a key component of the in vivo microenvironment, enables propagation of functional adult stem cells in culture for the first time. We expect these experimental approaches will be broadly applicable to other adult stem cell types and ultimately will profoundly impact regenerative medicine by enabling generation of functional stem cell populations for use in clinical cell-based therapies.

Chronic electrical stimulation of the brain has become a standard surgical therapy for Parkinson's disease, with many studies demonstrating excellent outcomes without any serious complications. Recently this surgical intervention has also been applied to various other neurological diseases, such as involuntary movement disorders, intractable pain, and psychological conditions including depression and obsessive-compulsive disorder. This comprehensive, up-to-date textbook will meet the needs of all who wish to learn more about the application of deep brain stimulation and will provide a sound basis for safe and accurate surgery. The book comprises two main parts, the first of which presents relevant anatomical and functional background information on the basal ganglia, thalamus, and other brain structures as well as on the mechanism of brain stimulation. The second part describes clinical studies on deep brain stimulation, covering results in a range of movement disorders and psychiatric diseases and also important aspects of instrumentation and technique. The authors are outstanding scientists and experts in the field from across the world. This book will be welcomed by all young neurosurgeons, neurologists, psychiatrists, and other medical staff who are interested in electrical stimulation of the brain for the treatment of neurological disorders.

Meniscal degeneration often precedes cartilage degeneration, and effective detection and treatment can be critical in preventing osteoarthritis. The meniscus is a heterogeneous tissue, and obtaining information on the varying characteristics of meniscal regions is important in investigating such strategies. However, no current method exists that can detect such meniscal heterogeneity in the tissue matrix. In addition, the lack of quantitative information on meniscal heterogeneity hinders the development an effective, long-term solution that can treat degeneration in the meniscus. The purpose of this dissertation was thus 1) to find quantitative characteristics that defined meniscal heterogeneity and 2) to evaluate non-invasive diagnostic methods that could reflect the matrix tissue properties and detect meniscal heterogeneity. To accomplish the first goal, gene expression profiles of meniscal cells were statistically analyzed to identify quantitative markers that could distinguish between different regions of the meniscus, describing its heterogeneous properties. This information was then used to evaluate cell sources for meniscal tissue engineering, demonstrating the potential application of these quantitative markers in developing an effective treatment for meniscal degeneration. Secondly, in order to detect meniscal heterogeneity, which is reflected in the changing tissue properties within the tissue, magnetic resonance imaging was used. The potential of the imaging parameters T1[rho] and T2 relaxation times in detecting various meniscal tissue properties, including the matrix composition and mechanical properties, was examined. Ultimately, such information would be useful in identifying internal degenerative changes that take place in the matrix of the tissue prior to macroscopic injuries. In this study, both T1[rho] and T2 relaxation times showed variation with tissue properties but were highly correlated with one another, indicating that only one imaging parameter might be necessary as a diagnostic tool in a clinical setting. In addition, an exploratory aim visualized the internal secondary collagen network in the meniscus and examined its deformation in different mechanical loading positions. This work significantly adds to the understanding of the heterogeneous properties of the meniscus and the potential of magnetic resonance imaging parameters as detection markers. It contributes to the advancement of diagnosis and treatment strategies for meniscal degeneration, which has further implications for preventing osteoarthritis progression.

[alpha] [beta] T cells are central mediators of the adaptive immune system, tasked with cytotoxic functions and coordinating the B cell and innate immune responses. The T cell response relies upon the T cell receptor, rendered hugely diverse through V(D)J recombination, sampling peptides bound to MHC molecules to instill antigen specificity to the immune response. However, the number of possible peptide-MHC greatly outstrips the theoretical number of possible T cell receptors and surpasses the total number of T cells in any given organism by an even larger margin. The basis for how T cell receptors can be cross-reactive enough to ensure all possible antigens can be recognized while retaining enough specificity to avoid promiscuous T cell activation and autoimmunity has not been systematically examined. To address this, I harness a manmade system to generate large degrees of molecular diversity, yeast display (introduced in Chapter 1), to directly assay the degree and mechanism of T cell receptor cross reactivity. Upon exhaustively examining the peptide-MHC recognition repertoire for five T cell receptors (in Chapter 2), I find a surprisingly limited degree of diversity in the recognized sequences. Instead, cross-reactivity is accomplished via relatively conservative mutations in the T cell receptor contact epitope mated to a larger degree of mutation elsewhere in the presented peptide. Even the most seemingly diverse sequences recognized by any T cell receptor are recognized in structurally similar ways and can be connected via intermediate related sequences. I then leverage these close relationships to find naturally occurring peptide ligands for T cell receptors with a high rate of success. In Chapter 3, I further refine our system to find even lower affinity peptide-MHC ligands, relevant for T cell development, through evolving a piece of 'molecular velcro' that provides an additional point of attachment between the peptide and T cell receptor while preserving discrimination between binding and nonbinding peptides.

Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor. Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in GBM, and the most common variant is EGFRvIII. Here we report that EGFRvIII is a novel cancer stem cell (CSC) or tumor initiating cell marker in GBM. EGFRvIII expression is restricted to sub-regions and sporadic cells within the tumor and EGFRvIII is frequently co-expressed in the putative CSC CD133+ population. EGFRvIII gene and protein expression can be maintained when primary GBM are cultured as tumor derived neurospheres and is lost when spheres are exposed to differentiating conditions. Furthermore, cells that express both EGFRvIII and CD133 display the greatest self-renewal and tumor initiating abilities when compared to the single positive or double negative populations. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved across the tumor despite focal expression. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII expression. EGFRvIII defined a hierarchy and epigenetic mechanisms played a role in maintaining heterogeneous EGFRvIII expression, suggesting that drugs which modulate the epigenome might be used successfully in glioblastoma tumors. To assess a broad applicability of our findings to other tumor types, we investigated EGFRvIII expression and amplification in primary breast carcinoma. Our analyses confirmed the presence of EGFRvIII, but in the absence of amplification or rearrangement of the EGFR locus. Interestingly, EGFRvIII was often expressed in a subset of tumor cells and was co-expressed in the putative CSC CD44+/CD24-/low population. EGFRvIII-expressing cells had increased expression of stem cell and epithelial-mesenchymal transition (EMT) associated genes and increased in vitro sphere formation and in vivo tumor formation compared to non-expressing cells. Mechanistically, EGFRvIII mediated its effects through the Wnt/[beta]-catenin pathway. Collectively, this data suggests a novel function for EGFRvIII in tumorigenesis and further supports the use of EGFRvIII-targeted therapy in these tumor types.

Prevention Science: An Epidemiological Approach -- Individual Physical, Cognitive, and Emotional Vulnerability Across the Life Course: Benchmarks and Developmental Challenges -- Benchmarks, Developmental Challenges, and Risks During the Prenatal and Infancy Period -- Childhood and the Entry into Adolescence: A Pivotal Period in Health-Related Behaviors and Prevention -- Adolescence and Early Adulthood -- Stressors and Vulnerabilities in Middle and Old Age: Opportunities for Prevention -- Environmental Influences and Implications for Intervention Development -- Family -- School Influences on Child and Youth Development -- Peer Networks -- Risk and Resilience Processes in Single-Mother Families: An Interactionist Perspective -- Environmental Influences: The Workplace and Mental Health-Models, Vulnerability Factors, and Interventions -- An Integrated Prevention Science Model: A Conceptual Foundation for Prevention Research -- Design of Prevention Interventions -- Implementation Science and the Effective Delivery of Evidence-Based Prevention -- Factors Affecting Implementation: Cultural Adaptation and Training -- Measuring Fidelity -- Research Design -- Translating the Intervention Approach into an Appropriate Research Design: The Next-Generation Adaptive Designs for Effectiveness and Implementation Research -- The Epidemiologic Case-Crossover and Case-Control Approaches in Prevention Research -- The Use of Simulation Models in Public Health with Applications to Substance Abuse and Obesity Problems -- Meta-analysis in Prevention Science -- Mixed Methods Research Design for Prevention Science: Methods, Critiques, and Recommendations -- Analytic Methods -- Latent Class Analysis in Prevention Science -- Discrete-Time Survival Analysis in Prevention Science -- Using Mediation and Moderation Analyses to Enhance Prevention Research -- Advances in Missing Data Models and Fidelity Issues of Implementing These Methods in Prevention Science -- Cost Analysis and Policy -- Economic Analysis and Policy Studies: Special Challenges in the Prevention Sciences -- Strengthening Prevention Science to Ensure Effectiveness of Intervention in Practice: Setting up an International Agenda.

The outcome of infectious disease depends on the ability of the pathogen to grow, the effectiveness of the host immune response, and the degree of damage the host incurs. A considerable number of the molecular components that participate in host-microbe interactions have been identified, yet the dynamics of the interactions between these components remain unclear. In this thesis, I explore various aspects of infection dynamics by examining a lethal-septic disease in Drosophila melanogaster caused by Listeria monocytogenes infection. By leveraging a combination of experimental approaches and mathematical modeling, I determined how varying the magnitude of individual parameters such as immune induction, microbe load, and damage production leads to changes in overall host health. Experimental measurement of the in-host bacterial growth, the dose response curves of antimicrobial peptide expression relative to bacterial loads, and the dose response curve of host survival relative to bacterial loads, defined as tolerance, informed the logic of the mathematical model. The dynamics of these parameters are best described by four-parameter (baseline, maximal, slope, and half-maximal concentration (EC50)) sigmoid functions. Given that microbe growth, immune induction and tolerance follows sigmoid dynamics, we inferred that host damage also follows sigmoid dynamics. These findings suggest that there are four general classes of variation in microbe growth, immune induction, host damage, and tolerance to infection. The mechanisms underlying each individual class of variation likely differ, and this implies that patients suffering from infection encounter different dynamical problems. To improve the efficacy of treatment, the dynamical problem must be identified, and the treatment strategy should be tailored accordingly. To understand the molecular underpinnings of different dynamical problems during infection, I compared the gene expression profiles across infection, antibiotic treatment, and recovery of fly lines that varied in the ability to control bacterial growth, defined as resistance, and tolerance. A mutation in CG2247 leads to a resistance defect to L. monocytogenes infection. CG2247 mutants have a 10-fold greater decrease in proPhenoloxidase-A1 (proPO-A1) expression compared to wild type, and the expression of proPO-A1 fails to return to baseline upon antibiotic treatment. proPO-A1 is a critical mediator of melanization induced by the immune response. Melanization both isolates and destroys invading microbes. Loss of CG2247 leads to an impaired melanization response, which explains the resistance defect. I also examined the gene expression profiles of the RAL359 line, which has a tolerance defect (decreased EC50) and a Pcmt mutant line, which has a defect in both resistance and tolerance (decreased EC50). The molecular mechanisms underlying the phenotypes of these two fly lines remain unclear. The molecular details underlying these different dynamical problems will inform the development of strategies for controlling the parameters of the sigmoid relationships we observe during infection.

"With rapid advancement in technology and materials in total knee arthroplasty (TKA), long-term survival and function of the total knee is now more and more dependent on restoring accurate limb alignment, precise component position and optimum soft-tissue balance. Proper technique is key to ensuring this and is all the more crucial and challenging to achieve in arthritic knees with severe and complex deformities. Correction of such knee deformities forms an important part of TKA for orthopedic surgeons working in both emerging and developed nations. Deformity Correction in Total Knee Arthroplasty fills the void that exists in treating severe and complex knee deformities and the use of computer-navigation in TKA. It covers the principles of deformity correction and soft-tissue balancing in primary TKA in an illustrative, step-wise and algorithmic fashion. Starting with the initial key step of preoperative planning, this book goes on to specifically describe how to deal with different types of deformities encountered in patients who undergo TKA - varus, valgus, flexion, hypertension, rotational and extra-articular deformities - as well as the stiff knee, the unstable knee, osteotomies in primary TKA and postoperative pain management and rehabilitation. This focused how-to manual includes plentiful images and clear, concise text from authors who have performed thousands of TKAs, making it a must-have reference for any surgeon unfamiliar or frequently confronted with this type of procedure."--Publisher's website.

Diagnosis -- History taking and the medical record -- The screening physical examination -- Vital signs, anthropometric data, and pain -- Non-regional systems and diseases -- The skin and nails -- The head and neck -- The chest : chest wall, pulmonary, and cardiovascular systems; the breasts -- Abdomen, perineum, anus, and rectosigmoid -- The urinary system -- The female genitalia and reproductive system -- Male genitalia and reproductive system -- The spine, pelvis and extremities -- The nervous system -- The mental status, psychiatric, and social evaluations -- The preoperative evaluation -- Principles of diagnostic testing -- Common laboratory tests.

Osteoarthritis is a debilitating disease that affects 27 million Americans. Major risk factors for osteoarthritis include mechanical injury and obesity. Prolonged exposure to mechanical overload in the knee joint, either by injury, malalignment, or obesity, is associated with early onset of osteoarthritis. Recent evidence demonstrates that adipose tissue is a metabolically active and produces systemic biofactors known as adipokines associated with numerous diseases including cardiovascular disease, hypertension, insulin resistance, rheumatoid arthritis, and osteoarthritis. Interestingly, obesity is a significant risk factor for hand osteoarthritis, suggesting a biologic link between obesity and osteoarthritis that is perhaps mediated through adipokines. While many studies investigating in vitro osteoarthritic degradation have focused on cartilage tissue, the menisci has received relatively little attention despite it's important functional role in joint stability and load transfer in the knee. The purpose of this thesis was to explore the relative susceptibility of cartilage and meniscal tissue degradation to in vitro mechanical overload and adipokine exposure using an immature bovine tissue explant model. To explore the injury response, explants of cartilage and meniscal tissues were compressed at various strain rates to create a spectrum of peak injury forces and cultured for up to nine days post-injury. To investigate whether adipose tissue and adipokines can biochemically induce changes in cartilage and meniscal tissues, explants of cartilage and meniscal tissue were incubated with infrapatellar fat pad or individual adipokines and assessed for altered matrix metabolism. Overall, results indicate that, while mechanically robust, meniscal tissue is vulnerable to biologic damage induced by mechanical overload and adipokines. We also demonstrate for the first time that meniscal tissue is more catabolically sensitive to adipokines than cartilage tissue. These results provide evidence that obesity-driven degradation of knee joint could be biochemically mediated and suggest meniscal degradation as a possible early event in osteoarthritis development.

The revised DeLee & Drez's Orthopaedic Sports Medicine covers the surgical, medical, and rehabilitation/injury prevention topics related to athletic injuries and chronic conditions with coverage of both pediatric and aging athletes; important non-orthopaedic conditions involved in the management of the athlete; rapidly evolving techniques; and sports-related fractures. It aids in understanding rehabilitation and other therapeutic modalities in the context of return to play. It also covers arthroscopic techniques, including ACL reconstruction, allograft cartilage transplantation, rotator cuff repair, and complications in athletes, as well as injury prevention, nutrition, pharmacology, and psychology in sports.

Defining organs at risk is a crucial task for radiation oncologists when aiming to optimize the benefit of radiation therapy, with delivery of the maximum dose to the tumor volume while sparing healthy tissues. This book will prove an invaluable guide to the delineation of organs at risk of toxicity in patients undergoing radiotherapy. The first and second sections address the anatomy of organs at risk, discuss the pathophysiology of radiation-induced damage, and present dose constraints and methods for target volume delineation. The third section is devoted to the radiological anatomy of organs at risk as seen on typical radiotherapy planning CT scans, with a view to assisting the radiation oncologist to recognize and delineate these organs for each anatomical region head and neck, mediastinum, abdomen, and pelvis. The book is intended both for young radiation oncologists still in training and for their senior colleagues wishing to reduce intra-institutional variations in practice and thereby to standardize the definition of clinical target volumes.

What is delirium in critical care? -- How common is delirium in critical care? -- What does delirium look like in critical care? -- Delirium in critical care? -- How does it happen? -- Delirium -- What causes it? Risk factors -- Why is it important? -- How do we diagnose it? -- How to prevent delirium? -- Treatment of delirium in critical care -- Mental capacity and restraints -- End of life care -- What's the future?

"In the United States, approximately 14 million people have had cancer and more than 1.6 million new cases are diagnosed each year. However, more than a decade after the Institute of Medicine (IOM) first studied the quality of cancer care, the barriers to achieving excellent care for all cancer patients remain daunting. Care often is not patient-centered, many patients do not receive palliative care to manage their symptoms and side effects from treatment, and decisions about care often are not based on the latest scientific evidence. The cost of cancer care also is rising faster than many sectors of medicine--having increased to 125 billion in 2010 from 72 billion in 2004--and is projected to reach 173 billion by 2020. Rising costs are making cancer care less affordable for patients and their families and are creating disparities in patients' access to high-quality cancer care. There also are growing shortages of health professionals skilled in providing cancer care, and the number of adults age 65 and older--the group most susceptible to cancer--is expected to double by 2030, contributing to a 45 percent increase in the number of people developing cancer. The current care delivery system is poorly prepared to address the care needs of this population, which are complex due to altered physiology, functional and cognitive impairment, multiple coexisting diseases, increased side effects from treatment, and greater need for social support. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis presents a conceptual framework for improving the quality of cancer care. This study proposes improvements to six interconnected components of care: (1) engaged patients; (2) an adequately staffed, trained, and coordinated workforce; (3) evidence-based care; (4) learning health care information technology (IT); (5) translation of evidence into clinical practice, quality measurement and performance improvement; and (6) accessible and affordable care. This report recommends changes across the board in these areas to improve the quality of care. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis provides information for cancer care teams, patients and their families, researchers, quality metrics developers, and payers, as well as HHS, other federal agencies, and industry to reevaluate their current roles and responsibilities in cancer care and work together to develop a higher quality care delivery system. By working toward this shared goal, the cancer care community can improve the quality of life and outcomes for people facing a cancer diagnosis."--Publisher's description.

"Delusions, in their many different manifestations, are central to the concepts of madness and psychosis. Yet what causes them remains in many ways a complete mystery. McKenna's Delusions is the first comprehensive attempt to tackle one of the most arresting phenomena in psychiatry: an in-depth and critical review of what delusions are, the forms they can take and how they might be explained from both psychological and biological perspectives. Delusions covers key topics such as the clinical features of delusions, the disorders they are seen in, other oddities that resemble them in both health and disease and the different approaches that have been taken to try and understand them. It is an essential book for psychiatrists and psychologists who work with delusional patients, as well as being of interest to neuroscientists engaged in research into major psychiatric disorders"-- Provided by publisher.

This book provides an overview of the demographic, clinical, and psychosocial context of dementia care. With its focus on patient and family perspectives, this book describes evidence-based approaches towards prevention, detection, and treatment of dementia that is like any other book. The text presents memory clinics, care management, home-based interventions, palliative care, family caregiver programs, specific to dementia care. Additionally, the text examines strategies to support transitions to acute care and long-term care. The text also places a special emphasis on measures of quality, cultural sensitivity, and implications for health care policy. Written by experts in the field, Dementia Care: An Evidence-Based Approach is an excellent resource for clinicians, students, healthcare administrators, and policymakers who aim to improve the quality of life of both the person with dementia and their informal caregiver.

This concise, pragmatic, pocket-sized book addresses neurological contributions to the diagnosis and management of dementia through a longitudinal examination of the work undertaken in a dedicated neurological dementia clinic. It covers the use of cognitive and non-cognitive screening instruments and their diagnostic utility and the use of other diagnostic investigations: neuroimaging, neurophysiology and neuropathology. The diagnostic mix is discussed in terms of both neuropsychological syndromes and neurological diagnoses, as is the use of conventional treatments for dementia and the impact of national directives (e.g. NICE, National Dementia Strategy) on day-to-day clinical practice. Dementia in Clinical Practice: A Neurological Perspective, Second Edition is an illustrated, practical resource for medical professionals involved in the assessment and management of dementia patients. It is of particular benefit to neurologists, psychiatrists, geriatricians, primary care practitioners and those working in the fields of neuropsychology, psychology, occupational therapy, speech and language therapy and nursing.

"Since the second edition of Dengue haemorrhagic fever: diagnosis, treatment, prevention and control was published by the World Health Organization (WHO) in 1997, the magnitude of the dengue problem has increased dramatically and has extended geographically to many previously unaffected areas. It was then, and remains today, the most important arthropod-borne viral disease of humans. Activities undertaken by WHO regarding dengue are most recently guided at the global policy level by World Health Assembly resolution WHA55.17 (adopted by the Fifty-fifth World Health Assembly in 2002) and at the regional level by resolution CE140.R17 of the Pan American Sanitary Conference (2007), resolution WPR/RC59.R6 of the WHO Regional Committee for the Western Pacific (2008) and resolution SEA/RC61/R5 of the WHO Regional Committee for South-East Asia (2008). This new edition has been produced to make widely available to health practitioners, laboratory personnel, those involved in vector control and other public health officials, a concise source of information of worldwide relevance on dengue. The guidelines provide updated practical information on the clinical management and delivery of clinical services; vector management and delivery of vector control services; laboratory diagnosis and diagnostic tests; and surveillance, emergency preparedness and response. Looking ahead, some indications of new and promising avenues of research are also described. Additional and more detailed specific guidance on the various specialist areas related to dengue are available from other sources in WHO and elsewhere, some of which are cited in the references. The contributions of, and review by, many experts both within and outside WHO have facilitated the preparation of this publication through consultative and peer review processes. All contributors are gratefully acknowledged, a list of whom appears under "Acknowledgements". These guidelines are the result of collaboration between the WHO Department of Control Neglected Tropical Diseases, the WHO Department of Epidemic and Pandemic Alert and Response, and the Special Programme for Research and Training in Tropical Diseases. This publication is intended to contribute to prevention and control of the morbidity and mortality associated with dengue and to serve as an authoritative reference source for health workers and researchers. These guidelines are not intended to replace national guidelines but to assist in the development of national or regional guidelines. They are expected to remain valid for five years (until 2014), although developments in research could change their validity, since many aspects of the prevention and control of dengue are currently being investigated in a variety of studies. The guidelines contain the most up-to-date information at the time of writing. However, the results of studies are being published regularly and should be taken into account. To address this challenge, the guide is also available on the Internet and will be updated regularly by WHO." - p. v.

Adipose tissue is found in diverse depots throughout the human body. The diversity of physiological specialization of these fat depots is reflected in the diverse depot-specific alterations seen in lipodystrophies and links between specific patterns of fat distribution and susceptibility to diseases, including Type II Diabetes and coronary artery disease. Previous studies, although focused on only 2 major fat depots (omental and abdominal subcutaneous), have identified numerous differences in metabolic, endocrine and developmental programs. We carried out a more extensive and higher resolution investigation of the anatomic specialization of white adipose tissue, based on 59 samples collected from 7 anatomically diverse fat depots, from 56 individuals. Using DNA microarrays we measured relative abundance of ~25,000 distinct mRNAs in each adipose tissue sample and in adipocytes and stromal-vascular cells isolated from each sample, and compared their gene expression patterns with ~120 samples representing diverse non-adipose tissues. Adipocytes from different regions of the body displayed distinct gene expression profiles. Characteristic patterns of expression of HOX genes distinguished adipocyte samples by site of origin; these patterns were recapitulated when adipocyte precursors from each site were cultured and differentiated ex vivo, suggesting that these genes may have a role in programming and/or maintaining depot-specific differentiation of adipocytes. Expression in adipocytes of 300 genes with major roles in energy metabolism showed both depot-dependent and inter-individual variation. Some of the patterns suggested important differences among anatomic depots in metabolic roles. For example, a set of genes involved in lipid uptake and storage and hormone-regulated lipolysis were generally most highly expressed in breast, pericolonic and omental adipocytes whereas genes involved in glycogen metabolism and de novo fatty acid synthesis were generally most highly expressed in breast and abdominal subcutaneous adipocytes, suggesting that these depots play a role as glucose buffers. Dozens of genes known or predicted to encode secreted molecular signals were highly expressed in adipocytes compared to either adipose stromal-vascular cells or other organs; many of these were differentially expressed among adipocyte depots. Some of these genes appear to be good candidates for encoding novel adipokines. In summary, we found extensive variation among adipose depots, as well as inter-individual variation, in global gene expression. Differences in genes linked to development, metabolism and cell-cell communication suggest new hypotheses relevant to depot-specific and general aspects of adipocyte biology.

Depression ranks as a leading mental health problem among Hispanic immigrants and their US-born children. And a wide array of issues - starting with the widespread stereotype of the "illegal immigrant" - makes the Latino experience of this condition differ from that of any other group. Depression in Latinos consolidates the conceptual, diagnostic, and clinical knowledge base on this salient topic, providing coverage from prevalence to prevention, from efficient screening to effective interventions. In this concise yet comprehensive volume, leading clinicians, researchers, and academics offer extensive research and clinical findings, literature reviews (e.g., an in-depth chapter on the Mexican American Prevalence and Services Survey), and insights gathered from first-hand experience in clinical practice. Perceptive information is offered on the most urgent and complex issues on depression in this diverse and dynamic population, including: (1) the impact language, culture, and societal factors have on depression and its diagnosis; (2) the most relevant assessment instruments; (3) how depression manifests among Latino children, youth, and seniors as well as in Latinas; (4) the relationship between depression and substance abuse; (5) the most effective evidence-based treatment methods; and (6) the efficacy of interventions for depression at the community level.

The degradation of misfolded secretory proteins is ultimately mediated by the ubiquitin-proteasome system in the cytoplasm, therefore endoplasmic reticulum-associated degradation (ERAD) substrates must be dislocated across the ER membrane through a process driven by the AAA ATPase p97/VCP. Derlins recruit p97/VCP and have been proposed to be part of the dislocation machinery. Here we report that Derlins are inactive members of the rhomboid family of intramembrane proteases and bind p97/VCP through C-terminal SHP boxes. Human Derlin-1 harboring mutations within the rhomboid domain stabilized mutant [alpha]-1 antitrypsin (NHK) at the cytosolic face of the ER membrane without disrupting the p97/VCP interaction. We propose that substrate interaction and p97/VCP recruitment are separate functions that are essential for dislocation and can be assigned respectively to the rhomboid domain and the C terminus of Derlin-1. These data suggest that intramembrane proteolysis and protein dislocation share unexpected mechanistic features.

"Novel drug delivery technologies strive to bypass challenging biological layers to elicit desired pharmacological activity. The skin, one of our key defensive barriers, is imperfect, and may allow certain topically applied substances or toxins to pass. The dermatokinetics of a drug determines the efficacy of treatment of skin disorders. Presenting the first comprehensive reference on this important area of research, Dermatokinetics of Therapeutic Agents includes a general overview of the theoretical as well as practical aspects of dermatokinetics and addresses the impact of nature of a drug delivery system on the dermatokinetics of drugs. Chapters and illustrations cover the introductory aspects significance, methods, and models used in dermatokinetic studies of therapeutic agents.Topics include: Theoretical Models for Dermatokinetics of Therapeutic Agents; Drug Delivery Approaches to Modulate Dermatokinetics of Drugs; Conventional Methods of Cutaneous Drug Sampling; Cutaneous Microdialysis; Sampling Substrates by Skin Permeabilization; Spectroscopic Techniques in Dermatokinetics Studies; Regulatory Perspective of Dermatokinetic Studies"--Provided by publisher.

Drs. Richard Usatine, John Pfenninger, Daniel Stulberg, and Rebecca Small, provides you with the clear, step-by-step guidance you need to provide these options to your patients. Full-color photographs and drawings in combination with high-definition narrated videos clearly demonstrate key procedures, including skin biopsies, cryosurgery, electrosurgery, botulinum toxin injections, and more. Incorporate key dermatologic and cosmetic procedures into your practice with coverage of using dermoscopy to more accurately detect skin cancer, the latest information on lasers, botulinum toxin injections and dermal fillers, the diagnosis and treatment of benign and malignant lesions, and more. Master dermatologic and cosmetic procedures thanks to more than 40 narrated, high-definition videos on DVD, demonstrating skin biopsies, cryosurgery, electrosurgery, and excision of skin cancers, cysts, and lipomas. See how to perform each procedure clearly from detailed, full-color photographs and drawings and step-by-step instructions. Maximize the value of providing dermatologic and cosmetic procedures with guidance on combination treatments as well as coding and billing details. Enhance your practice with step-by-step guidance to perform virtually any skin procedure in the office setting.

This book is a comprehensive introduction to ultrasonography of the skin, nails, and scalp as it relates to the assessment and diagnosis of dermatologic diseases. It provides a concise understanding of the diagnosis of dermatologic conditions through extensive high-resolution gray scale and color Doppler ultrasound images and presents classical correlations of clinical dermatologic lesions with sonographic and histologic findings.

"Dermatology, edited by world authorities Jean L. Bolognia, MD, Joseph L. Jorizzo, MD, and Julie V. Schaffer, MD, is an all-encompassing medical reference book that puts the latest practices in dermatologic diagnosis and treatment at your fingertips. It delivers more comprehensive coverage of basic science, clinical practice, pediatric dermatology, and dermatologic surgery than you'll find in any other source. Whether you're a resident or an experienced practitioner, you'll have the in-depth, expert, up-to-the-minute answers you need to overcome any challenge you face in practice."--Publisher's website.

This atlas, containing more than 300 color photos, focuses on those dermatologic conditions that are most common in ethnic skin or skin of color. It includes succinct explanations of each disease process, describes clinical findings, and presents key information on diagnosis and treatment. Individual chapters are devoted to pigmentary disorders, follicular disorders, hair and scalp disorders, eczemas, papulosquamous disorders, granulomatous disorders, connective tissue diseases, infectious diseases, scarring disorders, cutaneous neoplasms, photodermatoses and drug eruptions. The fact that this atlas covers skin disorders that affect patients of all ethnic backgrounds ensures that it will be of worldwide relevance. It will serve as a valuable reference for dermatologists and a range of other health care providers.

Dermatology Essentials, edited by world authorities Drs. Jean L. Bolognia, Julie V. Schaffer, Karynne O. Duncan, and Christine J. Ko, provides the quick answers you need on every important aspect of dermatology and guidance on their application in your day-to-day practice. Derived from the renowned authoritative reference work Dermatology, 3rd Edition, this on-the-go reference distills the essential information needed to quickly diagnose and manage a wide range of dermatologic disorders-without the need for any additional resources. Review or refresh your knowledge of the fundamentals and diagnostic approaches of skin disease with unique introductory chapters providing the basic principles of dermatology, bedside diagnostics, and clinical approach to a fever and rash - extremely helpful for the beginner. Visualize more of the conditions you see in practice with over 1,500 clinical images, illustrations, and schematics. Avoid diagnostic pitfalls using practical tables, intuitive artworks, and logical algorithms. Find answers fast with a highly user-friendly, "easy-in-easy-out" format and a wealth of tables and schematics for instant visual comprehension. Expedite decision making with easily recognizable DDx and Rx sections to provide rapid direct reference to the expert guidance and treatment recommendations. Downloadable worksheets are also available. Make the most of electronic functionality with access to the complete contents online and in various ebook formats - making it easy to teach impromptu on a tablet in the clinic, or conduct more formal lecturing.

New to this edition: Recognize the presentation of most major dermatopathology lesions through abundant high-resolution histopathology examples, with labels and pointers highlighting key aspects of each slide and providing additional clarity. Including 26 lectures by Dr. Elston, clinical and dermatopathology image atlases, and a virtual slide library. Easily focus on the most important "takeaways" and "must-knows" for each topic through the use of color key points, differential diagnosis, and pearls.

Part of the High-Yield Pathology Series, this title is designed to help you review the key pathologic features of skin disease, recognize the classic look of each disease, and quickly confirm your diagnosis. Its templated format, excellent color photographs, concise bulleted text, and authoritative content, will help you accurately identify more than 400 skin conditions. Find information quickly and easily with a templated, easy-to-reference format. Confirm your diagnoses with excellent color photographs that demonstrate the classic appearance of each disease. Find the answers you need fast with concise bulleted text. Depend on authoritative information from leading experts in the field.

With significant progress as new techniques to evaluate the pathology of the skin, this book satisfies the need to provide practical clinical information and concise criteria for pathologic diagnosis for pathologists and dermatologists looking for an up-to-date resource. This superb visual reference provides detailed instruction of the experience of both diagnostic pathology and clinical dermatology. Dermatopathology: Clinicopathological Correlations is a comprehensive but concise visual reference that contains specific features on the various clinical findings and histologic findings of skin diseases. It emphasizes criteria for diagnosis to help the trainee pathologist or dermatologist decipher the most important features and make clinical decisions quickly and effectively.

Drs. Peter Soyer, Giuseppe Argenziano, Rainer Hofmann-Wellenhof, and Iris Zalaudek explain all aspects of performing dermoscopy and interpreting results. With approximately 50% new clinical and dermoscopic images, valuable pearls and checklists, and you'll have everything you need to diagnose earlier and more accurately. Diagnose more accurately using the expanded section on testing tools for extra guidance on difficult cases. Gain a better visual understanding with approximately 50% new clinical and dermoscopic images that depict the appearance of benign and malignant lesions and feature arrows and labels to highlight important manifestations. Get better diagnostic results for less by learning how to successfully perform dermoscopy with this portable, to-the-point resource.

Bibliographic Standards Committee, Rare Books and Manuscripts Section, Association of College and Research Libraries in collaboration with the Cataloging Policy and Support Office of the Library of Congress.

Biological barriers prevent the uptake of many potentially harmful xenobiotics yet also limit the delivery and cellular entry of a variety of drugs to their targets. One approach to this problem selects only those compounds with appropriate properties, namely solubility in polar biological fluids yet also able to pass through the nonpolar cellular membrane. This restriction would therefore preclude the use of many polar (e.g. siRNA) and nonpolar (e.g. Taxol) compounds whose inherent physical properties cause problems with formulation, distribution or bioavailability. The research described herein utilizes an alternative strategy that involves molecular transporters, which are agents that, when attached to poorly soluble or poorly bioavailable drugs, produce conjugates that exhibit excellent water solubility and simultaneously an increased ability to cross tissue and cell barriers. Bioactivatable molecular transporter conjugates of the immunosuppressant drug Cyclosporin A incorporating disulfide linkers were developed, evaluated for their biological activity in vitro, and administered topically in an in vivo mouse model. In addition to the inherent physical properties limitation that prevents drug passage across the cell membrane, another significant contributor to the failure of many therapeutics is the overexpression of membrane proteins (e.g. P-glycoprotein or Pgp) that mediate the unidirectional efflux of drugs out of target cells, often doing so prior to the drug reaching its intracellular target. Bioactivatable oligoarginine transporter conjugates of Taxol, a substrate for Pgp, were prepared and shown to overcome efflux-mediated resistance in primary human ovarian cancer tissue ex vivo. The encapsulation of transporter conjugates inside biodegradable polymeric nanoparticles was also investigated as a way to achieve sustained release of transporter drug conjugates over extended periods of time, thereby avoiding metabolism or toxicity problems associated with a bolus administration of therapeutic agents. Nanoparticles encapsulating transporter-probe conjugates were formed using two different methods, and shown to release their encapsulated cargo over time under biologically relevant conditions.

The protein kinase C isozyme family has been implicated in a number of diseases representing the majority of the most significant challenges to global human health, including cancer, neurodegenerative diseases (Alzheimer's disease, depression, schizophrenia, etc.), cardiovascular disease, HIV/AIDS, diabetes, and chronic pain. As such, potent and selective modulation of this enzyme family using small molecule ligands designed for a particular function has tremendous therapeutic potential. A number of agents have been identified as ligands for the C1 domain of protein kinase C. Many of these compounds, including the endogenous ligand diacylglycerol and the complex bryostatin family of natural products, act by inducing an initial activation event, resulting in the translocation of protein kinase C to the plasma membrane where it can participate in the phosphorylation of downstream serine and threonine residues. The bryostatins are complex macrolides isolated from the marine organism Bugula neritina. Although a number of agents from this family of natural products have been shown to be biologically active, bryostatin 1 in particular has garnered tremendous therapeutic interest owing to its remarkable potency and activity profile. Specifically, bryostatin 1 has been shown to stimulate apoptosis, bolster the immune system, reverse multidrug resistance, synergize with other anticancer agents, enhance memory and learning in rodent models through the induction of synapse formation (synaptogenesis), reverse the effects of stroke in animal models, and induce latent HIV in vitro. As a result of this activity profile, bryostatin 1 is currently in phase I and II clinical trials for cancer treatment and is being advanced to the clinic for the treatment of Alzheimer's disease. However, despite its remarkable clinical potency (often ~ 1 mg is required for a 8 week treatment cycle in humans), the extremely low supply of bryostatin 1 prohibits its continued human clinical use and investigation for the treatment of additional therapeutic indications. In an effort to address the issues associated with the supply and unoptimized nature of a number of complex natural product protein kinase C ligands, the Wender group developed a pharmacophore model for C1 domain binding in the mid 1980s. This resulted in the design and synthesis of highly simplified, functional protein kinase C ligands based on the diacylglycerol scaffold. Additionally, structurally simplified, synthetically accessible bryostatin analogs were designed and shown to have comparable or even superior potency relative to bryostatin 1 for protein kinase C binding and in vitro anticancer activity. Described herein is the design, synthesis, and biological evaluation of a series of macrocyclic diacylglycerol analogs in an effort to improve protein kinase C affinity by reducing the entropic penalty of the binding event relative to the endogenous linear diacylglycerols. The binding affinity was found to be highly dependent on macrocycle size, with the most potent analog being up to two orders of magnitude more potent than the linear diacylglycerols (consistent with previous reports). Moreover, these analogs were prepared in a step-economical fashion (3-4 steps from commercial materials). Additionally, the design and synthesis of members of the first series of B-ring tetrahydropyran bryostatin analogs produced in the Wender group is reported. The use of a novel, high yielding Prins macrocyclization allowed for the retention of the synthetic convergency that has become a hallmark of the B-ring dioxane analogs produced previously in the Wender group. Several compounds from this B- ring tetrahydropyran class were found to be among the most potent analogs produced to date (with respect to protein kinase C affinity and in vitro anticancer activity). Despite the high potency and synthetic accessibility of the previously reported bryostatin analogs, these compounds lacked the ability to activate protein kinase C isozymes (as measured by their ability to induce the translocation of the enzyme from the cytosol to the plasma membrane) with a high degree of selectivity but were not equally non-selective either. The ability to tune isozyme selectivity has tremendous therapeutic potential and, in an effort to address this challenge, a series of A-ring functionalized, B-ring tetrahydropyran analogs was designed and synthesized using the Prins macrocyclization methodology. It was found that the C8 geminal dimethyl group on the A-ring in combination with C7 hydroxyl functionality imparts selectivity for the conventional protein kinase C [Beta]I over the novel protein kinase C [lowercase Delta}. Alternatively, C8 geminal dimethyl functionality in combination with C7 acetate functionality results in a high degree of non-selectivity for these isoforms. C13 functionalization was found to increase the potency of this already highly active analog class. Finally, several of the B-ring tetrahydropyran bryostatin analogs were shown to synergize with taxol in a human leukemia cell line. Additionally, a lead B-ring dioxane bryostatin analog was shown to be capable of inhibiting tumor growth in vivo in a transgenic mouse lymphoma model. Protein kinase C was implicated in this activity by monitoring the phosphorylation of downstream proteins as well as by performing inhibitor studies. This lead analog was also shown to induce apoptosis in a number of human B- and T-lymphocytes. The apoptotic induction observed in the murine cell line used for this pilot in vivo study was found to be independent of direct cell cycle effects. Significantly, this represents the first academic report of bryostatin analog efficacy and safety in vivo.

My graduate studies have focused on the design, synthesis, and biological evaluation of novel probe and drug delivery technologies. This research has explored the development of new molecular transporter scaffolds with a focus on step economy and translational costs as well as evaluation of their uptake and delivery properties in cells and animals. Chapter 1 provides a historical context and overview of guanidinium-rich molecular transporter technology. Chapter 2 describes the development of a new family of guanidinium-rich oligocarbonate molecular transporter which are flexibly and efficiently assembled by a one-step oligomerization strategy. These novel oligocarbonate transporters were shown to exhibit excellent uptake properties both in cells and animal models. Chapter 3 is directed at the utility of an oligomerization approach to generate molecular transporters by the design, synthesis, and evaluation of new aphipathic co-oligomers for the delivery of siRNA, an oligonucleotide cargo of intense therapeutic interest. Amphipathic carbonate co-oligomers were prepared by an oligomerization strategy and demonstrated to effectively package, deliver, and release functional siRNA in cells. Chapter 4 describes the effects of a branched guanidinium array on the transport and delivery efficiency of releasable dendrimeric guanidinium-rich transporters. These transporters were synthesized and demonstrated to deliver and release a small molecule for turnover by its intracellular target enzyme by bioluminescence assays in cells and transgenic animal models. Chapter 5 describes the design, synthesis, and preliminary biological evaluation of lipidated molecular transporter derivatives of the immunosuppressant drug rapamycin for topical delivery.

My graduate studies have focused on the development of novel drug delivery technologies of research, clinical, and industrial significance. More specifically, my research has focused on the design, synthesis, and application of guanidinium-rich molecular transporters for the delivery of siRNA into cells. My studies have also focused on using molecular transporters to develop the first molecular method to deliver cargo into algae, and on the development of new strategies to control the timing and amount of drug or probe release in cells. Though all of this research is fundamentally based on organic chemistry, these projects have broad applications in research, industrial and clinical settings. Chapter 1 reviews the strategies that have been developed for the delivery of siRNA in both cells and animals. Rather than divide the field by chemical type (e.g. peptide vs. protein) or disease indication, this review categorizes siRNA deliver agents by the identity of their cationic moiety for siRNA complexation. Guanidinium-containing delivery vectors are presented, as are vectors containing ammonium and phosphonium groups. Highlighting this field by cationic moiety reveals how little research has been done to compare the effects of the cation's identity on deliver efficacy, toxicity, and pharmacokinetics. Chapter 2 describes the design, synthesis, and evaluation of guanidinium-rich amphipathic oligocarbonate molecular transporters for the complexation, delivery, and release of siRNA in cells. The synthetic ease of the metal-free carbonate oligomerization to synthesize these transporters afforded fast access to a series of transporters that systematically probed the functionality required for effective complexation, delivery, and release of siRNA. Transporters were characterized and evaluated for biological activity in immortalized human keratinocytes. The transporters discovered in this study were highly effective, with target gene silencing of up to 90% observed. Chapter 3 focuses on efforts towards expanding the scope of both the chemical space and cell types tested in the delivery of siRNA with amphipathic oligocarbonate molecular transporters. These second generation delivery systems have improved physical properties, including smaller and more stable particle sizes, relative to their first generation counterparts described in Chapter 2. These transporters delivered siRNA to primary keratinocytes, melanoma cells, and ovarian cancer cells. Chapter 4 details the development of the first molecular method for the delivery of small molecule probes and large protein cargos into algal cells. It was shown that oligoarginine could facilitate the uptake of fluorescein, or the larger, FAM-streptavidin protein, into cells. A catalytically active protein was delivered into cells and was shown to maintain catalytic activity even after delivery. Chapter 5 describes the design of new strategies to control the timing and amount of cargo released inside cells. Efforts towards a novel linker carrying two copies of drug or probe are described, as well as the combination of microneedles and luciferin-transporter conjugates for transdermal delivery in vivo.

In this work, a function-oriented array of simplified analogs of the daphnane diterpene orthoester class of natural products bearing palmitate, phenyl, or phenylacetyl orthoesters was synthesized starting from commerically available starting materials via a key late stage common diversification intermediate. These families of novel compounds were evaluated for both selective PKC activation and growth inhibition of K562 (myleogenous leukemia) cancer cells. While these analogs showed no growth inhibitory activity in K562 cells up to concentrations of 10 micromolar, they did display varying profiles of PKC activation. One analog in particular demonstrated the ability to activate and cause translocation of conventional PKC b1 and novel PKC d to the same extent as resiniferonol, a potent natural resiniferonoid. A second analog, however, was found to activate novel PKC d selectively over conventional PKC b1; surprisingly, resiniferonol did not share this selectivity profile. Because the simplified, functional analogs synthesized in this study were shown to activate PKC while having no growth inhibitory activity, these compounds should be further investigated for their potential as therapeutic leads for the treatment of diseases like Alzheimer's or Parkinson's, in which (selective) activation of PKC could serve a therapeutic purpose without being plagued by growth inhibitory pathways.

Using SAS, SPSS, and R, this book addresses design and analysis aspects in enough detail so that readers can apply statistical methods to their own longitudinal studies. This edition includes a new chapter on testing models that involve moderation and mediation, a new chapter on QALYs and QTWiST specific to clinical trials, and recent methodological developments for the analysis of trials with missing data. It also presents revised discussions of multiple comparisons procedures that focus on the integration of HRQoL outcomes with other study outcomes using gatekeeper strategies.

A balance between complexity and functional capabilities has been explored since the first years of multi-fingered robotic hands. In an age where DC motors are the de facto standard for actuation in robotics, the problem of needing to operate in a human-sized world puts severe constraints and limits on actuator size and placement in hands. While many successful examples of fully-actuated designs exist, these designs generally reflect the trade-offs and sacrifices imposed by such constraints. In that light, underactuation, employing fewer actuators than degrees of freedom, has gained attention as a method to achieve many of the functional capabilities of fully-actuated hands with fewer constraints on actuators and transmissions. Underactuated hands also have distinct advantages over fully actuated hands, especially when used on mobile robots, due to their reduced weight and control complexity, and the potential for increased robustness. However there is typically a trade-off in terms of reduced controllability or manipulability when handling grasped objects. When designing underactuated hands, extra care must be taken during the design process to ensure that such hands will grasp a wide range of object sizes and shapes robustly, particularly when friction is low and uncertain. Despite these concerns, underactuated hands have become increasingly popular in robotic and prosthetic applications. Robotic hands are also a venue in which novel, secondary mechanisms are often found. Devices such as differentials, valves, clutches, and low-power, shape-changing actuators have been used to improve grasp robustness on a wider range of objects and allow users more grasping and manipulation options. However, the location and placement of secondary actuators has not been studied in a comprehensive way with respect to the types of actuation methods possible. This is due in part to the lack of general analytic tools which enable designers to rapidly investigate their designs prior to the prototyping stage. Additionally, much of the analysis in the field of robotic hands is done once basic design choices have already been made, making subsequent analyses specific only to a set of design parameters specific to those choices. The same point can be made regarding quality metrics, which suffer from fragmented utilization due to the many different emphases placed on different design requirements. The primary goal of this thesis is to provide a framework for the analysis and evaluation of underactuated robotic hands. The first chapter discusses both the broad motivations for studying robotic hands and the specific contributions of this thesis. The next chapter reviews relevant designs from literature, analyses that have accompanied them, uses of secondary devices in underactuated hands, and the progress that dynamics simulators have made towards representing reality. In the next chapters, the issues related to modeling abstract, generic hand designs is discussed, and a kinematic framework is introduced to derive the force relationships between actuator and grasped object for many mechanisms commonly encountered in underactuated hands. Chapter 6 discusses difficulties associated with solving static force equations, and several methods are introduced to accomplish this. The last of these options relies on three-dimensional rigid-body dynamic simulations to evaluate the performance of compliant, underactuated mechanisms which may encounter conditions such as coulomb friction in contact and and damping at the joints. In the next chapters, these force relationships are derived and discussed for specific hand designs in the context of a force-field representation, and several performance metrics are derived which measure a hand's ability both to acquire and retain objects. The benefits of secondary actuation mechanisms are then discussed with two specific examples. First is the SRI/Stanford/Meka hand, a tendon-driven, compliant, underactuated hand capable of locking individual joints. Second is a mechanism implemented on the Seabed Hand, which increases the range of graspable objects and allows users to selectively change grasp properties based on their specific control needs. Finally, the impacts of friction are discussed, and the trends from simulations are compared with experimental data. From these experiments the benefits of secondary mechanisms can be demonstrated in a frictional world as well.

This dissertation describes the design, implementation, and experimentation of an autonomous free-climbing robot, Capuchin. The objective of our project is to create a multi-limbed robot capable of climbing vertical terrain autonomously using techniques similar to those used by human free climbers. When a "free" climber climbs a steep crag or an artificial climbing wall, she uses nothing else but her hands and feet to make contact with terrain features such as holes, cracks, ledges or protrusions. Unlike "aid" climbing, which uses special equipments, tools, or engineered features, free climbing only relies on friction at the contacts between the climber and the terrain. In order to make a multi-limbed robot climb in a similar way, four fundamental challenges must be addressed: robot design, sensing, motion planning and motion control. Our work focuses on robot design (including sensors) and motion control. However, our robot, Capuchin, is an integrated system including a simplified sensing system and a pre-existing motion planner running off-line. A good robot design can increase the inherent ability of the robot to climb complex terrain. It may also lead to better performance and make other issues easier, such as motion planning and control. A four-limb structure was chosen after consideration of the robot's capability and complexity. Simulation was used during the design process to optimize performance, in particular to maximize the workspace reachable by the end-effectors (fingers). Sensors have been selected to allow the robot to both acquire information about the terrain and control its motion. Each finger is equipped with a camera. Vision feedback allows the robot controller to accurately dock the finger on a terrain feature at a location computed by the planner. It also allows modifying a planned trajectory in real-time, when the terrain differs slightly from the model that had been used by the planner or when other small errors occur (for instance, if the robot slips slightly at a contact). Each finger is additionally equipped with a force sensor that gives the magnitude and orientation of the reaction force at a contact. The four force sensors are used by the robot controller to maintain the robot in quasi-static equilibrium, by adjusting the robot posture and the joint torques when needed, so that the reaction forces at the contact point continuously within their Coulomb friction cones. A two-stage motion planner previously developed by Bretl and Hauser for free-climbing and other multi-limbed robots navigating on challenging and irregular terrain is used in this work. This planner decomposes a climbing motion into a sequence of moves, each performed with a fixed set of robot-terrain contacts (this set is called a "stance"). The transition at the end of each move consists of either breaking a contact or making a new one. The planner first computes a sequence of stances. Next it computes a trajectory for the move to be performed at each stance. If it fails to find a move at one step, it considers another sequence of stances. The core part of our research has been the design of the motion controller. The main problem we had to solve is a multi-contact force control problem. One of our most important findings has been the following: for quasi-static climbing, it is not necessary, even not desirable, to continuously control the forces exerted by the robot at the contact points. Instead, it is preferable to continuously monitor these forces and perform joint torque adjustments only when some reaction forces get too close to the boundaries of the friction cones or to their maximal magnitude. This strategy was not obvious when we started our research. In fact, we first developed a motion controller that continuously adjusted joint torques to keep measured reaction forces as close as possible to the terrain normals at the contact points. But computing these adjustments is rather time consuming. Moreover, this approach leads the robot to perform delicate adjustments frequently. As a result, robot motion was neither as smooth, nor as reliable as we would have liked. Instead, our new approach, which we call "lazy" force control, leads to a faster servo rate and much smoother motion. Our experiments show that on average adjustments only amount for a small percentage (less than 10%) of the total time spent climbing. They also demonstrate that Capuchin can reliably climb vertical artificial climbing walls autonomously and can handle small errors in the terrain model used by the planner.

Using hybrid x-ray/MR (XMR) systems for image guidance during interventional procedures can enhance the diagnosis and treatment of neurologic, oncologic, cardiovascular, and other disorders. XMR suites have become more available, with various vendors offering dual-modality solutions. These systems combine the three-dimensional imaging capabilities and excellent soft tissue contrast provided by MR with the high spatial/temporal resolution and accurate device tracking provided by x-ray. To eliminate system compatibility concerns, the suites typically have long travel distances between MR and x-ray components. As a result, switching between modalities requires shuttling the patient several meters from one system to the other. Because patients typically have critically placed monitoring systems and intravenous lines for drug delivery and anesthesia, the cumbersome shuttling process impedes repeated switching between the modalities. To circumvent the hurdles associated with alternating between modalities, we proposed a close proximity hybrid system design in which a c-arm fluoroscopy unit is placed immediately adjacent to a closed bore MR system with a minimum distance of 1.2 meters between the x-ray and MR imaging field of views. Placing the x-ray system so close to the MR bore requires an x-ray tube capable of operating in a relatively strong MR fringe field environment. Existing rotating anode x-ray tube designs fail within MR fringe field environments because the magnetic fields alter the electron trajectories in the x-ray tube and act as a brake on the induction motor, reducing the rotation speed of the anode. In my work, I have developed (1) techniques to correct for the altered electron trajectories and (2) a novel motor design that eliminates the reduced rotation speed of the anode. Altering electron trajectories between the cathode and anode affects the location, size, and shape of the x-ray tube focal spot on the anode. I proposed a combination of approaches to control the trajectories. First, I derived an active magnetic shielding design using constrained optimization techniques that minimizes power consumption and heat deposition in the external deflection coils. I then adapted my shielding design to include rare earth permanent magnets, to further reduce the power and size requirements of the coils. Finally, I designed a split-focusing cup that controls the electron trajectories via electrostatic mechanisms, providing an alternative that is more space efficient and MR-compatible. High rotation speed of the anode is needed for sufficient instantaneous heat loading on the target area, to achieve the needed x-ray tube output. There is currently no available motor design to rotate the anode in the expected magnetic environment. To solve this problem, I designed a new motor that operates efficiently within the fringe field. The design is analogous to a modified three-pole brushed DC motor, with the radial component of the MR fringe field replacing the permanent magnet stator field used in conventional brushed DC motors. The motor support bearings provide rotating electrical contacts, while feedback signals from a position sensor control electrical commutation. A vacuum compatible prototype of the proposed motor design was assembled, and its performance was evaluated at various field strengths and orientations. Combining the control mechanisms for the electron trajectories with the new motor design yields a robust x-ray tube capable of operating in fringe fields with magnitudes on the order of 0.1 to 0.2 T.

Optical MEMS (Micro-Electro-Mechanical Systems) is an enabling technology that realizes miniaturized optical systems with high functionality and excellent performance. In this dissertation, two novel miniaturized optical systems are presented for applications in optical communication and biomedical imaging. In Part I, a multi-functional MEMS tunable optical filter are described, which is a key element for dynamic wavelength provisioning in reconfigurable optical networks and communication systems. This filter is built based on MEMS platform technology that allows large vertical mirrors (311 [mu]m x 450 [mu]m x 40 [mu]m) to be micro-assembled on actuated platforms to enable compact tunable optical filters with large apertures and high-quality optical mirrors with very low scattering losses. Besides, electrostatic combdrive actuators connected to the MEMS platforms provide independent and continuous control of the center wavelength and the optical bandwidth. The filter has been tested by integrating it in a 10Gb/s communication system. The performance of the MEMS tunable filter is demonstrated for amplified spontaneous emission (ASE) rejection and wavelength selection. In PART II, a 3-D MEMS scanning system utilizing 2-D lateral and 1-D vertical MEMS scanners is introduced for use in miniature in vivo dual-axis confocal (DAC) microendoscopes, which is an emerging biomedical-imaging technology with high resolution, good tissue penetration, large field of view, and ability to provide both reflectance and fluorescence contrast images. Both MEMS scanners are fabricated exclusively by front-side processing to enable compact and robust structures that facilitate handling and packaging for miniaturized optical instrumentation. Co-operation of a 2-D lateral scanner and a 1-D vertical scanner enables fast 3-D microscopy over a volume that measures 340[mu]m by 236[mu]m by 286[mu]m. This part describes the principle of the all-MEMS-based 3-D scanning DAC microscopy that gives the functionality of OCT (real-time vertical cross-section imaging) to a confocal microscope.

Over the last several years advances and miniaturization of technology have allowed legged robots to move from the research laboratory to the real world, as evidenced by the large number of flexible platforms only recently available. These platforms are successful, but fall short of capitalizing on the biggest advantage of legs: the ability for high speed locomotion over unstructured terrain. Additionally, no current articulated legged robot is able to perform both static and truly dynamic locomotion, as the actuation technology is not conducive to these two very different regimes of operation. Currently, machines that are dynamic are unable to walk or position themselves accurately, and machines that function very well with static motions are unable to move dynamically. The bipedal robot TRIP (Tendonized Running Inspired Platform) was built to study dynamic maneuvering and control of an articulated legged robot with high-inertia legs. Each leg includes an inelastic tendon which couples ankle joint rotations to knee joint rotations, resulting in simplified effective dynamics and control, and a high degree of passive stabilization with dynamic maneuvers. A hybrid pneumatic-electric actuator was built and tested while driving a knee joint; this actuator is capable of precise positioning, as well as highly energetic thrusting. It will be shown that static and dynamic maneuvers are attainable with a tendon-coupled ankle, and that a tendon allows simpler dynamic control through the concept of impulse compensation, and through the use of passive stabilization from the kinematics resulting from the tendon. Second, it will be shown that the hybrid actuator is superior in some respects to current available technology, both by specification, and by experimental results of static and dynamic maneuvers achieved through its use. And third, using a general heuristic-based control algorithm developed for various sized bipedal machines, dynamic maneuvers are possible with a high leg-to-body moment of inertia ratio, which would show that the control strategy takes into account the dynamics of the legs during high speed locomotion.

"Combining the latest thinking about mixed methods research designs with practical, step-by-step guidance, the Second Edition of Designing and Conducting Mixed Methods Research now covers six major mixed methods designs. Authors John W. Creswell and Vicki L. Plano Clark walk readers through the entire research process, from formulating questions to designing, collecting data, and interpreting results and include updated examples from published mixed methods studies drawn from the social, behavioral, health, and education disciplines."--pub. desc.

Purified DNA serves as a template for a wide array of analysis techniques, ranging from sequencing to PCR and hybridization assays. DNA analysis can be used for clinical diagnosis, for forensic investigation, and for a range of research purposes. These analysis techniques improve each year, but they are all constrained by the availability of purified DNA. DNA is typically derived from raw biological samples that contain a host of other molecular species, including proteins, lipids and metal ions. These species can inhibit analysis of the DNA, so purification of DNA from complex sample matrices is a necessary precursor to analysis. Typically, DNA purification is performed using either liquid-liquid extraction or solid-phase extraction, both of which require manual labor, involve toxic chemicals, and are difficult to miniaturize. Isotachophoresis (ITP) is an alternative method for DNA purification that does not rely on specialized surface chemistry or toxic chemical species. Instead, ITP uses electric fields to selectively pre-concentrate DNA from a raw sample, and simultaneously separate it from inhibiting species. ITP purification of DNA has been demonstrated from human serum, plasma, and whole blood, and the same technique has been used to purify RNA from bacteria in human blood and urine. Until recently, the parameters governing extraction efficiency, throughput, and separation quality in ITP purification were not well established. This thesis is focused on rational analysis for designing and optimizing ITP systems for rapid, high quality DNA purification.

"Clear, polished, and stimulating presentations are as important to the scientific profession as they are to business, yet most scientists never receive formal training in the creation, delivery, and evaluation of such material." ... "Designing Science Presentations provides visually intensive guidance at every step-from the construction of original figures to the presentation and delivery of those figures in papers, slideshows, posters, and websites." --Excerpts from publisher's description.

"As simple and straightforward as two health professionals conferring over the telephone or as complex and sophisticated as robotic surgery between facilities at different ends of the globe, telehealth is an increasingly frequent component in healthcare. A primer on the human factors issues that can influence how older adults interact with telehealth systems, Designing Telehealth for an Aging Population: A Human Factors Perspective examines the new ways patients and healthcare providers communicate to achieve the same or better outcomes than with traditional face-to-face healthcare.The authors examine older adult capabilities and provide standards and guidelines for telehealth design, enlivened by clinical examples and tutorials on human factors methodologies. They take a systematic look at how the use of human factors principles can facilitate the successful development, deployment, and maintenance of telehealth technology to better serve the aging population. The authors have carefully stayed away from academic writing, distilling their experience in the form of basic observations and principles drawn from their work. They include suggested readings at the end of each chapter that supply the research underpinning their recommendations. The first reference to cover older adult users in an area that will only get bigger, this book sets itself apart by providing focused coverage of the human factors issues specific to aging populations and practical advice on how to accommodate them"-- Provided by publisher.

Understanding human brain function is one of the most important endeavors in modern science. There is growing evidence that cognitive functions are executed by large-scale networks, comprising multiple interacting anatomically-connected brain areas. Although considerable progress has been made in understanding which specific brain areas are involved in particular cognitive functions, very little is known about the integrative functioning of large-scale brain networks. This is due in part to the lack of methods to pursue this line of research. This dissertation describes computational methods for detecting and characterizing large-scale human brain networks, combining data from task-free functional magnetic resonance imaging (fMRI) and structural diffusion tensor imaging (DTI), two complementary brain imaging modalities. Application of our methods to task-free fMRI and DTI data obtained from a wide range of subject populations provided new insights into how large-scale human brain networks develop, mature, and get disrupted in psychiatric and neurological disorders. More generally, this work demonstrates the power of our multimodal network-analytic approach to obtain a system-level understanding of brain function across the human lifespan.

Due to the sequential nature of magnetic resonance imaging (MRI) data acquisition, correction of image artifacts originating from involuntary patient motion is essential for reliable diagnostic quality. Especially during MRI scans of certain patient populations such as children, elderly or patients with certain medical conditions (e.g. stroke, Parkinson's), motion correction methods must be incorporated into the MR imaging protocol for adequate image quality. With increased demands for higher resolution or time-resolved examinations (e.g. functional MRI), examination times also increase and even willing patients might have trouble staying still during the course of the examination. The first part of this thesis provides a method for retrospective correction of head motion artifacts using a multi-shot spiral-in \& out readout and parallel-imaging based iterative image reconstruction. The spiral-in part provided a low resolution image that was used for measurement of head motion. Due to rotational motion, locally undersampled areas appear in MR acquisition space (i.e., k-space), which violate the Nyquist theorem and cause artifacts even after motion correction. These artifacts were addressed through the data redundancy provided by multiple receiver channels that is present in modern receiver coils and an iterative conjugate-gradient based reconstruction. This method was then applied to diffusion tensor imaging (DTI) with multi-shot readout. Since DTI uses directional gradients to encode diffusion, rotational motion causes the image contrast to change, and it becomes incorrect to combine data with varying diffusion encodings on them. To address this issue, a non-linear conjugate gradient based reconstruction is presented and it is shown that this method provided more accurate description of white matter pathways compared to traditional methods. In the second part of this thesis, a prospective motion correction system using an optical tracking device is presented. Such systems are preferable compared to retrospective navigator-based methods due to various reasons, such as ability to perform motion correction independent of the MR data acquisition and immunity to spin history effects. The system proposed used a single camera mounted on the head coil and a self-encoded checkerboard marker mounted on the patient's forehead. Results on structural and diffusion imaging revealed that prospective motion correction outperforms retrospective navigator-based schemes. In the last part of the thesis, entropy-based retrospective autofocusing was used in combination with motion data obtained from prospective tracking to remove residual motion artifacts in the images. This method was especially useful for removing errors caused by inaccurate cross-calibration between the scanner and camera frame-of-references. It was also shown that prospective tracking can be the enabling technology for autofocusing in 3D acquisitions.

In the era of rapid high-throughput DNA sequencing and increasing bioinformatic capabilities to analyze large amounts of biological data, it is especially important to continue to develop high-throughput experimental proteomic methods. Probing physical interactions among proteins and nucleic acids is a powerful approach to gain insight into their functional relationships. Microfluidic tools are of great potential value to this field because they make it possible to run hundreds or thousands of independent experiments in parallel and at a high spatial density. Here I present and explain MITOMI (mechanically induced trapping of molecular interactions), an in vitro method that was initially created to measure the affinities of transcription factors binding to DNA. I contributed to the development of the system so it could be applied to mapping protein-protein interaction networks, and used it to study the interactions of E. coli RNA polymerase in order to better understand the regulation of bacterial transcription. I also extended the utility of MITOMI by adapting it to be able to measure interaction kinetics and to more efficiently measure affinities. With the ability to discover interactions at a large scale and to quantitatively characterize them on the same platform, MITOMI constitutes a valuable contribution to proteomic methodology.

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Clearinghouse (NGC): A comprehensive database of evidence-based
clinical practice guidelines and related documents.MedlinePlus: A repository of health
information from the National Library of Medicine. Links are from
trusted sites. No advertising, no endorsement of commercial companies
or productsLPCH
CareNotes via MicroMedex: Patient education handouts customized by
LPCH clinical staffMicromedex
Lab Advisor: Evidence based laboratory test informationA drug database organized by generic
name, trade name and drug class.LPCH /
Stanford Hospital Formulary.A
goldmine of trusted consumer health information from the world's
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A
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Over 10,000 notes outline the status of specific infections
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Large number of high quality software
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